There is considerable evidence that stress can affect the immune system of animals. While similar data exist for men, less attention has been given to women. Perhaps one reason for this disparity is the potential complicating factor of ovarian hormones. Hormonal fluctuations associated with the menstrual cycle, pregnancy or menopause may modify the impact of stress on immune function and contribute to gender differences in immunologically-related disorders. Our first grant, for which this is a revised renewal, directly studies the relationship between hormonal state and the effects of psychological stress on the immune system of women. Using a unique A-B-A design, naturally cycling women are assessed for stress-induced changes in cardiovascular, endocrine and immunologic measures during the follicular stage and again, after complete pharmacologic suppression of ovarian hormones, produced by the GnRH agonist, Lupron. The contribution of estrogen is determined by comparing women who are allowed to resume their cycles with those kept on Lupron and given estradiol. In the 21 months since the start of this grant, 25 women, have completed or are currently enrolled. Analyses are presented on the first 24 women, 16 experimental and 8 controls, who have completed the A1- B stages. Subjects had similar baseline values for all measures at visit 1, although state, but not trait, anxiety was higher in experimentals at both visits. Stress reduced the response of peripheral blood lymphocytes to mitogens, the % of CD4+ cells, the CD4+/CD8+ ratio, and IgG production. NK activity, both % specific lysis and lytic units, was increased by stress. Unstressed controls did not show these changes. Stress elevated systolic and diastolic blood pressure, heart rate, plasma norepinephrine (NE) and epinephrine (E).The number and percentage of T-cells, percentage of CD4+ cells, CD4+/CD8+ ratio, number of B-cells, serum IL-1a, and basal plasma levels of NE and DBP increased significantly from the first (follicular) to the second (Lupron-suppressed) visit in experimentals but not controls. There was also a trend for the percentage of NK cells to decrease in visit 2. However, changes in several other cardiovascular, endocrine and immunologic measures from visit #1 to #2 suggested possible habituation or practice effects. We are asking for two more years of funding to complete the study as originally designed, with the addition of the measurement of IL-6, and include another, potentially important experimental group - B (Lupron Suppression)-A1 (follicular) A1 (follicular). This group would allow us to disentangle the effects of habituation to the stressors from the effects of suppressing hormonal levels.